Clinical spectrum of
            <i>SCN2A</i>
            mutations expanding to Ohtahara syndrome

Nakamura, Kazuyuki; Kato, Mitsuhiro; Osaka, Hitoshi; Yamashita, Sumimasa; Nakagawa, Eiji; Haginoya, Kazuhiro; Tohyama, Jun; Okuda, Mitsuko; Wada, Takahito; Shimakawa, Shuichi; Imai, Katsumi; Takeshita, Saoko; Ishiwata, Hisako; Lev, Dorit; Lerman‐Sagie, Tally; Cervantes-Barragán, David E.; Villarroel, Camilo E.; Ohfu, Masaharu; Writzl, Karin; Stražišar, Barbara Gnidovec; Hirabayashi, Shinichi; Chitayat, David; Reid, Denise; Nishiyama, Kiyomi; Kodera, Hirofumi; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Miyake, Noriko; Hayasaka, Kiyoshi; Matsumoto, Naomichi; Saitsu, Hirotomo

doi:10.1212/wnl.0b013e3182a43e57

Cited by 189 publications

(181 citation statements)

References 40 publications

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“…Mutations of this gene are associated with noteworthy clinical variability ranging from familial benign seizures to generalized epilepsy with febrile seizures or epileptic encephalopathy. 35 The patient presented only febrile seizures, whereas her mother had benign generalized epilepsy with absences.…”

Section: Discussionmentioning

confidence: 99%

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

et al. 2014

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We analyzed by next-generation sequencing (NGS) 67 epilepsy genes in 19 patients with different types of either isolated or syndromic epileptic disorders and in 15 controls to investigate whether a quick and cheap molecular diagnosis could be provided. The average number of nonsynonymous and splice site mutations per subject was similar in the two cohorts indicating that, even with relatively small targeted platforms, finding the disease gene is not an univocal process. Our diagnostic yield was 47% with nine cases in which we identified a very likely causative mutation. In most of them no interpretation would have been possible in absence of detailed phenotype and familial information. Seven out of 19 patients had a phenotype suggesting the involvement of a specific gene. Disease-causing mutations were found in six of these cases. Among the remaining patients, we could find a probably causative mutation only in three. None of the genes affected in the latter cases had been suspected a priori. Our protocol requires 8-10 weeks including the investigation of the parents with a cost per patient comparable to sequencing of 1-2 medium-to-large-sized genes by conventional techniques. The platform we used, although providing much less information than whole-exome or whole-genome sequencing, has the advantage that can also be run on 'benchtop' sequencers combining rapid turnaround times with higher manageability.

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Section: Discussionmentioning

confidence: 99%

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

et al. 2014

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“…KCNQ2 and SCN2A genetic testing should be considered for patients with EOEE, although genotype-phenotype correlations are not yet well understood 60 . However, it has been recognized that KCNQ2 screening should be performed for refractory neonatal seizures of unknown origin.…”

Section: Impact Of the New Genetic Findings In Clinical Practicementioning

confidence: 99%

Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice

Gonsales

Montenegro

Soler

et al. 2015

Arq. Neuro-Psiquiatr.

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Recent advances in molecular genetics led to the discovery of several genes for childhood epileptic encephalopathies (CEEs). As the knowledge about the genes associated with this group of disorders develops, it becomes evident that CEEs present a number of specific genetic characteristics, which will influence the use of molecular testing for clinical purposes. Among these, there are the presence of marked genetic heterogeneity and the high frequency of de novo mutations. Therefore, the main objectives of this review paper are to present and discuss current knowledge regarding i) new genetic findings in CEEs, ii) phenotype-genotype correlations in different forms of CEEs; and, most importantly, iii) the impact of these new findings in clinical practice. Accompanying this text we have included a comprehensive table, containing the list of genes currently known to be involved in the etiology of CEEs.

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“…15,16 Furthermore, epilepsy is a common feature of neurodevelopmental disorders, including autism spectrum disorder and intellectual disability, with many shared causative genes such as CHD2, GRIN2B, SCN2A, and SYNGAP1. 15,[17][18][19][20][21][22] Several recent studies have highlighted the usefulness of DES in clinical pediatric neurology practice, emphasizing a high diagnostic rate and impact on genetic counseling and patient management. 8,9,23 Data from small cohorts of patients with severe epilepsies also highlight the utility of DES for improving molecular diagnoses.…”

Section: Introductionmentioning

confidence: 99%

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

Helbig

Hagman

Shinde

et al. 2016

Genetics in Medicine

311

247

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Purpose:To assess the yield of diagnostic exome sequencing (DES) and to characterize the molecular findings in characterized and novel disease genes in patients with epilepsy. Methods:In an unselected sample of 1,131 patients referred for DES, overall results were compared between patients with and without epilepsy. DES results were examined based on age of onset and epilepsy diagnosis.Results: Positive/likely positive results were identified in 112/293 (38.2%) epilepsy patients compared with 210/732 (28.7%) patients without epilepsy (P = 0.004). The diagnostic yield in characterized disease genes among patients with epilepsy was 33.4% (105/314). KCNQ2, MECP2, FOXG1, IQSEC2, KMT2A, and STXBP1 were most commonly affected by de novo alterations. Patients with epileptic encephalopathies had the highest rate of positive findings (43.4%).A likely positive novel genetic etiology was proposed in 14/200 (7%) patients with epilepsy; this frequency was highest in patients with epileptic encephalopathies (17%). Three genes (COQ4, DNM1, and PURA) were initially reported as likely positive novel disease genes and were subsequently corroborated in independent peer-reviewed publications.Conclusion: DES with analysis and interpretation of both characterized and novel genetic etiologies is a useful diagnostic tool in epilepsy, particularly in severe early-onset epilepsy. The reporting on novel genetic etiologies may further increase the diagnostic yield.

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Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome

Abstract: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.

Cited by 189 publications

References 40 publications

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

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